Phosphonomethyl-imidazo[1,2-A]pyrimidine-2-carboxylic acid compounds for treatment of neurotoxic injury

ABSTRACT

A class of phosphonomethyl-imidazo[1,2-a]pyrimidine-2-carboxylic acid compounds is described for treatment to reduce neurotoxic injury associated with anoxia or ischemia which typically follows stroke, cardiac arrest, hypoglycemia or perinatal asphyxia. The treatment includes administration of a compound of this class alone or in a composition in an amount effective as an antagonist to inhibit excitotoxic actions at major neuronal excitatory amino acid receptor sites. Compounds of most interest are those of the formula: ##STR1## wherein each of R 1 , R 2  and R 6  is independently selected from hydrido, alkyl, allyl, cycloalkyl, cycloalkylalkyl, phenyl and benzyl; wherein Y m  is --CH 2  -- or --CH 2  --CH 2  --; where m is one; wherein X is one or more groups attachable at one or more of the 5-, 6- and 7-ring positions of the imidazo[1,2-a]pyrimidine ring system; wherein each x and T is independently selected from hydrido, halo, alkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, alkenyl, alkynyl, phenyl, benzyl, hydroxy, hydroxyalkyl, alkoxy, phenoxy, alkoxyalkyl, benzyloxy, cyano, alkanoyl, alkylthio, arylthio and amino; or a pharmaceutically-acceptable salt thereof.

RELATED APPLICATION

This is a divisional of application Ser. No. 07/982/819 filed Nov.30,1992 U.S. Pat. No. 5,302,586 which is a continuation-in-part of U.S.application Ser. No. 07/810,242 filed 19 Dec. 1991 abandoned.

FIELD OF THE INVENTION

This invention is in the field of clinical neurology and relatesspecifically to a class of compounds, compositions and methods forneuro-protective purposes such as controlling chronic or acuteneurotoxic injury or brain damage resulting from neuro-degenerativediseases. For example, these compounds are particularly useful fortreating neurotoxic injury which follows periods of anoxia or ischemiaassociated with stroke, cardiac arrest, hypoglycemia or perinatalasphyxia.

BACKGROUND OF THE INVENTION

Unlike other tissues which can survive extended periods of hypoxia,brain tissue is particularly sensitive to deprivation of oxygen orenergy. Permanent damage to neurons can occur during brief periods ofhypoxia, anoxia or ischemia. Neurotoxic injury is known to be caused oraccelerated by certain excitatory amino acids (EAA) found naturally inthe central nervous system (CNS). Glutamate (Glu) is an endogenous aminoacid which has been characterized as a fast excitatory transmitter inthe mammalian brain. Glutamate is also known as a powerful neurotoxincapable of killing CNS neurons under certain pathological conditionswhich accompany stroke and cardiac arrest. Normal glutamateconcentrations are maintained within brain tissue by energy-consumingtransport systems. Under low energy conditions which occur duringconditions of hypoglycemia, hypoxia or ischemia, cells can releaseglutamate. Under such low energy conditions the cell is not able to takeglutamate back into the cell. Initial glutamate release stimulatesfurther release of glutamate which results in an extracellular glutamateaccumulation and a cascade of neurotoxic injury.

It has been shown that the sensitivity of central neurons to hypoxia andischemia can be reduced by either blockage of synaptic transmission orby the specific antagonism of postsynaptic glutamate receptors [see S.M. Rothman et al, Annals of Neurology, Vol. 19, No. 2 (1986)]. Glutamateis characterized as a broad spectrum agonist having activity at threeneuronal excitatory amino acid receptor sites. These receptor sites arenamed after the amino acids which selectively excite them, namely:Kainate (KA), N-methyl-D-aspartate (NMDA or NMA) and quisqualate (QUIS).Glutamate is believed to be a mixed agonist capable of binding to andexciting all three receptor types.

Neurons which have ERA receptors on their dendritic or somal surfacesundergo acute excitotoxic degeneration when these receptors areexcessively activated by glutamate. Thus, agents which selectively blockor antagonize the action of glutamate at the EAA synaptic receptors ofcentral neurons can prevent neurotoxic injury associated with anoxia,hypoxia or ischemia caused by stroke, cardiac arrest or perinatalasphyxia.

Aminophosphonic acids have been investigated as neurotransmitterblockers [see M. N. Perkins et al, Neuroscience Lett., 23,333 (1981);and J. Davies et al, Neuroscience Lett., 21, 77 (1981)]. In particular,compounds such as 2-amino-4-(2-phosphonomethyl-phenyl)butyric acid and2-(2-amino-2-carboxy) ethylphenylphosphonic acid have been synthesizedfor evaluation as antagonists in blocking the action of theneurotransmitter compounds L-glutamic acid and L-aspartic acid [K.Matoba et al, "Structural Modification of Bioactive Compounds II.Syntheses of Aminophosphonic Acids", Chem. Pharm. Bull., 32, (10)3918-3925 (1984)].

An analogue of 2-amino-7-phosphonoheptanoic acid, namely3-2-carboxypiperazin-4-yl)propyl-1-phosphonic acid [CPP], has beenreported as a potent and selective NMDA antagonist in an evaluation ofCPP binding to rat brain hippocamal tissue [D. E. Murphy et al, J,Pharmacol. Exp. Ther., 240 (3), 778-784 ( 1987)].

U.S. Pat. No. 4,657,899 to Rzeszotarski et al, which issued, describes aclass of w-[2-phosphonoalkylenyl)phenyl]2-aminoalkanoic acidscharacterized as being selective excitatory amino acid neurotransmitterreceptor blockers. These compounds are mentioned for use asanticonvulsants, antiepileptics, analgesics and cognition enhancers.Typical compounds of the class include3-[2-phosphonomethylphenyl]-2-aminopropanoic acid and3-[2-(2-phosphonoethyl)phenyl]-2-aminopropanoic acid.

U.S. Pat. No. 4,918,064 to Cordi et al, which issued 17 Apr. 1990,describes a class of phosphonomethylphenylglycine compounds fortreatment to reduce neurotoxic injury associated with anoxia or ischemiawhich typically follows stroke, cardiac arrest or perinatal asphyxia.

Several classes of imidazopyrimidine compounds are known having variouspharmaceutical uses. For example, U.S. Pat. No. 4,532,243 to Tully,which issued 30 Jul. 1985, describes a series of5/7-alkylthio/alkoxyimidazo[1,2-a]pyrimidines as anxiolytic agents. U.S.Pat. No. 4,636,502 to Spitzer, which issued 13 Jan. 1987, describes aseries of 2-phenyl-imidazo[1,2-a]pyrimidines for use as inotropic agentsand vasodilators.

DESCRIPTION OF THE INVENTION

Control of neuropathological processes and the neuro-degenerativeconsequences thereof in a subject is provided by treating the subjectsusceptible to neurotoxic injury with an anti-excitotoxic effectiveamount of a compound characterized in having activity as an antagonistat a major neuronal excitatory amino acid receptor site, such as theNMDA receptor site. Such antagonist compounds may be selected from aclass of imidazo[1,2-a]pyrimidine compounds defined by Formula I:##STR2## wherein A is selected from ##STR3## wherein B is selected from##STR4## wherein each of R¹ through R⁸ is independently selected fromhydrido, alkyl, allyl, cycloalkyl, cycloalkylalkyl, phenyl and benzyl;

wherein each of Y_(m) and Y_(n) is a spacer group independently selectedfrom one or more groups of the formula ##STR5## with the proviso thatthe total number of carbon atoms in each of Y_(m) or Y_(n) cannot exceedtwenty carbon atoms; wherein each of R⁹ and R¹⁰ is independentlyselected from hydrido, alkyl, cycloalkyl, halo, haloalkyl, phenyl,benzyl, hydroxy, hydroxyalkyl, alkoxy, phenoxy, alkoxyalkyl, benzyloxy,cyano and alkanoyl; wherein R⁹ and R¹⁰ may be taken together to form oxoor exomethylene; wherein each of R¹¹ and R¹² is independently selectedfrom hydrido, alkyl, haloalkyl, phenyl, hydroxyalkyl and alkoxyalkyl;wherein each of m and n is a number independently selected from zero tofour, inclusive;

wherein x is one or more groups attachable at one or more of the 5-, 6-and 7-ring positions of the imidazo[1,2-a]pyrimidine ring system;wherein each X and T is independently selected from hydrido, halo,alkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, alkenyl, alkynyl, phenyl,benzyl, hydroxy, hydroxyalkyl, alkoxy, phenoxy, alkoxyalkyl, benzyloxy,cyano, alkanoyl, alkylthio and arylthio, ##STR6## wherein each of R¹³,R¹⁴, R¹⁵ and R¹⁶ is independently selected from hydrido, alkyl andphenyl;

or a pharmaceutically-acceptable salt thereof.

Within the class of compounds of Formula I, there first sub-classconsisting of compounds of Formula II ##STR7## wherein each of R³, R⁴,R⁵ and R⁶ is independently selected from hydrido, alkyl, allyl,cycloalkyl, cycloalkylalkyl, phenyl and benzyl;

wherein each of Y_(m) and Y_(n) is a spacer group independently selectedfrom one or more groups of the formula ##STR8## with the proviso thatthe total number of carbon atoms in each of Y_(m) or Y_(n) cannot exceedten carbon atoms; wherein each of R⁹ and R¹⁰ is independently selectedfrom hydrido, alkyl, cycloalkyl, halo, haloalkyl, hydroxy, hydroxyalkyl,alkoxy, alkoxyalkyl and alkanoyl; wherein R⁹ and R¹⁰ may be takentogether to form oxo or exomethylene; wherein each of R¹¹ and R¹² isindependently selected from hydrido, alkyl, haloalkyl, phenyl,hydroxyalkyl and alkoxyalkyl; wherein m is a number selected from one tothree, inclusive; wherein n is a number selected from zero to three,inclusive;

wherein X is one or more groups attachable at one or more of the 5-, 6-and 7-ring positions of the tetrahydroimidazo [1,2-a]pyrimidine ringsystem; wherein each X and T is independently selected from hydrido,halo, alkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, alkenyl, alkynyl,phenyl, benzyl, hydroxy, hydroxyalkyl, alkoxy, phenoxy, alkoxyalkyl,benzyloxy, cyano, alkanoyl, alkylthio and arylthio, ##STR9## whereineach of R¹³, R¹⁴, R¹⁵ and R¹⁶ is independently selected from hydrido,alkyl and phenyl;

or a pharmaceutically-acceptable salt thereof.

Specific compounds of particular interest within Formula II arecompounds, and their pharmaceutically-acceptable salts, of the group ofcompounds consisting of

ethyl5-[(ethoxyphosphonamide)methyl]-imidazo[1,2-a]pyrimidine-2-carboxylate;

5-(phosphonamidemethyl)-imidazo[1,2-a]pyrimidine-2-carboxylic acid;

ethyl6-[(ethoxyphosphonamide)methyl]-imidazo[1,2-a]pyrimidine-2-carboxylate;

6(phosphonamidemethyl)-imidazo[1,2-a]pyrimidine-2-carboxylic acid;

ethyl 7-[(ethoxyphosphonamide)methyl]-imidazo[1,2-a]pyrimidine-2-carboxylate;

7-(phosphonamidemethyl)-imidazo[1,2-a]pyrimidine-2-carboxylic acid;

ethyl6-chloro-5-[(ethoxyphosphonamide)methyl]-imidazo[1,2-a]pyrimidine-2-carboxylate;

6-chloro-5-(phosphonamidemethyl)-imidazo[1,2-a]pyrimidine-2-carboxylicacid;

ethyl7-chloro-5-[(ethoxyphosphonamide)methyl]-imidazo[1,2-a]pyrimidine-2-carboxylate;

7-chloro-5-(phosphonamidemethyl)-imidazo[1,2-a]pyrimidine-2-carboxylicacid;

ethyl 5-(ethoxyphosphonamide)-imidazo[1,2-a]pyrimidine-2-carboxylate;

ethyl 5-ethoxyphosphonamide)-imidazo[1,2-a]pyrimidine-2-carboxylate,monohydrochloride;

5-phosphonamide-imidazo[1,2-a]pyrimidine-2-carboxylic acid;

ethyl5-[2-(ethoxyphosphonamide)-E-ethenyl]-imidazo[1,2-a]pyrimidine-2-carboxylate;

5-(2-phosphonamide-E-ethenyl)-imidazo[1,2-a]pyrimidine-2-carboxylicacid; and

5-(2-phosphonamideethyl)-imidazo[1,2-a]pyrimidine-2-carboxylic acid.

within the class of compounds of Formula I, there is a second sub-classconsisting of compounds of Formula III ##STR10## wherein each of R¹, R²and R⁶ is independently selected from hydrido, alkyl, allyl, cycloalkyl,cycloalkylalkyl, phenyl benzyl;

wherein each of Y_(m) and Y_(n) is a spacer group independently selectedfrom one or more groups of the formula ##STR11## with the proviso thatthe total number of carbon atoms in each of Y_(m) or Y_(n) cannot exceedten carbon atoms; wherein each of R⁹ and R¹⁰ is independently selectedfrom hydrido, alkyl, cycloalkyl, halo, haloalkyl, hydroxy, hydroxyalkyl,alkoxy, alkoxyalkyl and alkanoyl; wherein R⁹ and R¹⁰ may be takentogether to form oxo or exomethylene; wherein each of R¹¹ and R¹² isindependently selected from hydrido, alkyl, haloalkyl, phenyl,hydroxyalkyl and alkoxyalkyl; wherein m is a number selected from one tothree, inclusive; wherein n is a number selected from zero to three,inclusive;

wherein X is one or more groups attachable at one or more of the 5-, 6-and 7-ring positions of the imidazo[1,2-a] pyrimidine ring system;wherein each X and T is independently selected from hydrido, halo,alkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, alkenyl, alkynyl, phenyl,benzyl, hydroxy, hydroxyalkyl, alkoxy, phenoxy, alkoxyalkyl, benzyloxy,cyano, alkanoyl, alkylthio and arylthio, ##STR12## wherein each of R¹³,R¹⁴, R¹⁵ and R¹⁶ is independently selected from hydrido, alkyl andphenyl;

or a pharmaceutically-acceptable salt thereof.

Specific compounds of particular interest within Formula III arecompounds, and their pharmaceutically-acceptable salts, of the group ofcompounds consisting of

ethyl5-[(diethoxyphosphinyl)methyl]-imidazo[1,2-a]pyrimidine-2-carboxylate;

5-(phosphonomethyl)-imidazo[1,2-a]pyrimidine-2-carboxylic acid;

ethyl6-[(diethoxyphosphinyl)methyl]-imidazo[1,2-a]pyrimidine-2-carboxylate;

6-(phosphonomethyl)-imidazo[1,2-a]pyrimidine-2-carboxylic acid;

ethyl7-[(diethoxyphosphinyl)methyl]-imidazo[1,2-a]pyrimidine-2-carboxylate;

7-(phosphonomethyl)-imidazo[1,2-a]pyrimidine-2-carboxylic acid;

ethyl6-chloro-5-[(diethoxyphosphinyl)methyl]-imidazo[1,2-a]pyrimidine-2-carboxylate;

6-chloro-5-(phosphonomethyl)-imidazo[1,2-a]pyrimidine-2-carboxylic acid;

ethyl7-chloro-5-[(diethoxyphosphinyl)methyl]-imidazo[1,2pyrimidine-2-carboxylate;

7-chloro-5-(phosphonomethyl)-imidazo[1,2-a]pyrimidine-2-carboxylic acid;

ethyl 5-(diethoxyphosphinyl)-imidazo[1,2-a]pyrimidine-2-carboxylate;

ethyl 5-diethoxyphosphinyl)-imidazo[1,2-a]pyrimidine-2-carboxylate,monohydrochloride;

5-phosphono-imidazo[1,2-a]pyrimidine-2-carboxylic acid;

ethyl5-[2-(diethoxyphosphinyl)-E-ethenyl]-imidazo[1,2-a]pyrimidine-2-carboxylate;

5-(2-phosphono-E-ethenyl)-imidazo[1,2-a]pyrimidine-2-carboxylic acid;and

5-(2-phosphonoethyl)-imidazo[1,2-a]pyrimidine-2-carboxylic acid.

Within the class of compounds of Formula I, there is a third sub-classconsisting of compounds of Formula IV ##STR13## wherein each of R³, R⁴,R⁵, R⁷ and R⁸ is independently selected from hydrido, alkyl, allyl,cycloalkyl, cycloalkylalkyl, phenyl and benzyl;

wherein each of Y_(m) and Y_(n) is a spacer group independently selectedfrom one or more groups of the formula ##STR14## with the proviso thatthe total number of carbon atoms in each of Y_(m) or Y_(n) cannot exceedten carbon atoms; wherein each of R⁹ and R¹⁰ is independently selectedfrom hydrido, alkyl, cycloalkyl, halo, haloalkyl, hydroxy, hydroxyalkyl,alkoxy, alkoxyalkyl and alkanoyl; wherein R⁹ and R¹⁰ may be takentogether to form oxo or exomethylene; wherein each of R¹¹ and R¹² isindependently selected from hydrido, alkyl, haloalkyl, phenyl,hydroxyalkyl and alkoxyalkyl; wherein m is a number selected from one tothree, inclusive; wherein n is a number selected from zero to three,inclusive;

wherein x is one or more groups attachable at one or more of the 5-, 6-and 7-ring positions of the imidazo[1,2-a]pyrimidine ring system;wherein each X and T is independently selected from hydrido, halo,alkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, alkenyl, alkynyl, phenyl,benzyl, hydroxy, hydroxyalkyl, alkoxy, phenoxy, alkoxyalkyl, benzyloxy,cyano, alkanoyl, alkylthio and arylthio, ##STR15## wherein each of R¹³,R¹⁴, R¹⁵ and R¹⁶ is independently selected from hydrido, alkyl andphenyl;

wherein each of R³, R⁴, R⁵, R⁷ and R⁸ is independently selected fromhydrido, alkyl, allyl, cycloalkyl, cycloalkylalkyl, phenyl and benzyl;

or a pharmaceutically-acceptable salt thereof.

Specific compounds of particular interest within Formula IV arecompounds, and their pharmaceutically-acceptable salts, of the group ofcompounds consisting of

5-[(ethoxyphosphonamide)methyl]-imidazo[1,2-a]pyrimidine-2-carboxamide;

5-(phosphonamidemethyl)-imidazo[1,2-a]pyrimidine-2-carboxamide;

6-[(ethoxyphosphonamide)methyl]-imidazo[1,2-a]pyrimidine-2-carboxamide;

6-(phosphonamidemethyl)-imidazo[1,2-a]pyrimidine-2-carboxamide;

7-[(ethoxyphosphonamide)methyl]-imidazo[1,2-a]pyrimidine-2-carboxamide;

7-(phosphonamidemethyl)-imidazo[1,2-a]pyrimidine-2-carboxamide;

6-chloro-5-[(ethoxyphosphonamide)methyl]-imidazo[1,2a]pyrimidine-2-carboxamide;

6-chloro-5-(phosphonamidemethyl)-imidazo[1,2-a]pyrimidine-2-carboxamide;

7-chloro-5-[(ethoxyphosphonamide)methyl]-imidazo[1,2a]pyrimidine-2-carboxamide;

7-chloro-5-(phosphonamidemethyl)-imidazo[1,2-a]pyrimidine-2-carboxamide;

5-(ethoxyphosphonamide)-imidazo[1,2-a]pyrimidine-2-carboxamide;

5-ethoxyphosphonamide)-imidazo[1,2-a]pyrimidine-2-carboxamide,monohydrochloride;

5-phosphonamide-imidazo[1,2-a]pyrimidine-2-carboxamide;

5-[2-(ethoxyphosphonamide)-E-ethenyl]-imidazo[1,2a]pyrimidine-2-carboxamide;

5-(2-phosphonamide-m-ethenyl)-imidazo[1,2-a]pyrimidine-2-carboxamide;and

5-(2-phosphonamideethyl)-imidazo[1,2-a]pyrimidine-2-carboxamide.

Within the class of compounds of Formula I, there is a fourth sub-classconsisting of compounds of Formula V ##STR16## wherein each of R¹, R²,R⁷ and R⁸ is independently selected from hydrido, alkyl, allyl,cycloalkyl, cycloalkylalkyl, phenyl and benzyl;

wherein each of Y_(m) and Y_(n) is a spacer group independently selectedfrom one or more groups of the formula ##STR17## with the proviso thatthe total number of carbon atoms in each of Y_(m) or Y_(n) cannot exceedten carbon atoms; wherein each of R⁹ and R¹⁰ is independently selectedfrom hydrido, alkyl, cycloalkyl) halo, haloalkyl, hydroxy, hydroxyalkyl,alkoxy, alkoxyalkyl and alkanoyl; wherein R⁹ and R¹⁰ may be takentogether to form oxo or exomethylene; wherein each of R¹¹ and R¹² isindependently selected from hydrido, alkyl, haloalkyl, phenyl,hydroxyalkyl and alkoxyalkyl; wherein m is a number selected from one tothree, inclusive; wherein n is a number selected from zero to three,inclusive;

wherein X is one or more groups attachable at one or more of the 5-, 6-and 7-ring positions of the imidazo[1,2-a]pyrimidine ring system;wherein each X and T is independently selected from hydrido, halo,alkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, alkenyl, alkynyl, phenyl,benzyl, hydroxy, hydroxyalkyl, alkoxy, phenoxy, alkoxyalkyl, benzyloxy,cyano, alkanoyl, alkylthio and arylthio, ##STR18## wherein each of R¹³,R¹⁴, R¹⁵ and R¹⁶ is independently selected from hydrido, alkyl andphenyl;

pharmaceutically-acceptable salt thereof.

Specific compounds of particular interest within Formula V arecompounds, and their pharmaceutically-acceptable salts, of the group ofcompounds consisting of

5-[(diethoxyphosphinyl)methyl]-imidazo[1,2-a]pyrimidine-2-carboxamide;

5-(phosphonomethyl)-imidazo[1,2-a]pyrimidine-2-carboxamide;

6-[(diethoxyphosphinyl)methyl]-imidazo[1,2-a]pyrimidine-2-carboxamide;

6-(phosphonomethyl)-imidazo[1,2-a]pyrimidine-2-carboxamide;

7-[(diethoxyphosphinyl)methyl]-imidazo[1,2-a]pyrimidine-2-carboxamide;

7-(phosphonomethyl)-imidazo[1,2-a]pyrimidine-2-carboxamide;

6-chloro -5[(diethoxyphosphinyl)methyl]-imidazo[1,2a]pyrimidine-2-carboxamide;

6-chloro-5-(phosphonomethyl)-imidazo[1,2-a]pyrimidine-2carboxamide;

7-chloro-5-[(diethoxyphosphinyl)methyl]-imidazo[1,2a]pyrimidine-2-carboxamide;

7-chloro-5-(phosphonomethyl)-imidazo[1,2-a]pyrimidine-2-carboxamide;

5-(diethoxyphosphinyl)-imidazo[1,2-a]pyrimidine-2-carboxamide;

5-diethoxyphosphinyl)-imidazo[1,2-a]pyrimidine-2-carboxamide,monohydrochloride;

5-phosphono-imidazo[1,2-a]pyrimidine-2-carboxamide;

5-[2-(diethoxyphosphinyl)-E-ethenyl]-imidazo[1,2-a]pyrimidine-2-carboxamide;

5-(2-phosphono-E-ethenyl)-imidazo[1,2-a]pyrimidine-2-carboxamide; and

5-(2-phosphonoethyl)-imidazo[1,2-a]pyrimidine-2-carboxamide.

The term "hydrido" denotes a single hydrogen atom (H). This hydridogroup may be attached, for example, to an oxygen atom to form a hydroxylgroup; or, as another example, one hydrido group may be attached to acarbon atom to form a ##STR19## group; or, as another example, twohydrido groups may be attached to a carbon atom to form a --CH₂ --group.Where the term "alkyl" is used, either alone or within other terms suchas "haloalkyl" and "hydroxyalkyl", the term "alkyl" embraces linear orbranched radicals having one to about twenty carbon atoms or,preferably, one to about twelve carbon atoms. More preferred alkylradicals are "lower alkyl" radicals having one to about ten carbonatoms. Most preferred are lower alkyl radicals having one to about fivecarbon atoms. The term "cycloalkyl" embraces cyclic radicals havingthree to about ten ring carbon atoms, preferably three to about sixcarbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl andcyclohexyl. The term "haloalkyl" embraces radicals wherein any one ormore of the alkyl carbon atoms is substituted with one or more halogroups, preferably selected from bromo, chloro and fluoro. Specificallyembraced by the term "haloalkyl" are monohaloalkyl, dihaloalkyl andpolyhaloalkyl groups. A monohaloalkyl group, for example, may haveeither a bromo, a chloro, or a fluoro atom within the group. Dihaloalkyland polyhaloalkyl groups may be substituted with two or more of the samehalo groups, or may have a combination of different halo groups. Adihaloalkyl group, for example, may have two fluoro atoms, such asdifluoromethyl and difluorobutyl groups, or two chloro atoms, such as adichloromethyl group, or one fluoro atom and one chloro atom, such as afluorochloromethyl group. Examples of a polyhaloalkyl aretrifluoromethyl, 1,1-difluoroethyl, 2,2,2-trifluoroethyl, perfluoroethyland 2,2,3,3-tetrafluoropropyl groups. The term "difluoroalkyl" embracesalkyl groups having two fluoro atoms substituted on any one or two ofthe alkyl group carbon atoms. The terms "alkylol" and "hydroxyalkyl"embrace linear or branched alkyl groups having one to about ten carbonatoms any one of which may be substituted with one or more hydroxylgroups. The term "alkenyl" embraces linear or branched radicals havingtwo to about twenty carbon atoms, preferably three to about ten carbonatoms, and containing at least one carbon-carbon double bond, whichcarbon-carbon double bond may have either cis or trans geometry withinthe alkenyl moiety. The term "alkynyl" embraces linear or branchedradicals having two to about twenty carbon atoms, preferably two toabout ten carbon atoms, and containing at least one carbon-carbon triplebond. The term "cycloalkenyl" embraces cyclic radicals having three toabout ten ring carbon atoms including one or more double bonds involvingadjacent ring carbons. The terms "alkoxy" and "alkoxyalkyl" embracelinear or branched oxy-containing radicals each having alkyl portions ofone to about ten carbon atoms, such as methoxy group. The term"alkoxyalkyl" also embraces alkyl radicals having two or more alkoxygroups attached to the alkyl radical, that is, to form monoalkoxyalkyland dialkoxyalkyl groups. The "alkoxy" or "alkoxyalkyl" radicals may befurther substituted with one or more halo atoms, such as fluoro, chloroor bromo, to provide haloalkoxy or haloalkoxyalkyl groups. The term"alkylthio" embraces radicals containing a linear or branched alkylgroup, of one to about ten carbon atoms attached to a divalent sulfuratom, such as a methythio group. Preferred aryl groups are thoseconsisting of one, two, or three benzene rings. The term "aryl" embracesaromatic radicals such as phenyl, naphthyl and biphenyl. The term"aralkyl" embraces aryl-substituted alkyl radicals such as benzyl,diphenylmethyl, triphenylmethyl, phenylethyl, phenylbutyl anddiphenylethyl. The terms "benzyl" and "phenylmethyl" areinterchangeable. The terms "aryloxy" and "arylthio" denote radicalrespectively, aryl groups having an oxygen or sulfur atom through whichthe radical is attached to a nucleus, examples of which are phenoxy andphenylthio. The terms "sulfinyl" and "sulfonyl", whether used alone orlinked to other terms, denotes respectively divalent radicals SO andSO₂. The term "aralkoxy", alone or within another term, embraces an arylgroup attached to an alkoxy group to form, for example, benzyloxy. Theterm "acyl" whether used alone, or within a term such as acyloxy,denotes a radical provided by the residue after removal of hydroxyl froman organic acid, examples of such radical being acetyl and benzoyl."Lower alkanoyl" is an example of a more prefered sub-class of acyl. Theterm "amido" denotes a radical consisting of nitrogen atom attached to acarbonyl group, which radical may be further substituted in the mannerdescribed herein. The amido radical can be attached to the nucleus of acompound of the invention through the carbonyl moiety or through thenitrogen atom of the amido radical. The term "alkenylalkyl" denotes aradical having a double-bond unsaturation site between two carbons, andwhich radical may consist of only two carbons or may be furthersubstituted with alkyl groups which may optionally contain additionaldouble-bond unsaturation. For any of the foregoing defined radicals,preferred radicals are those containing from one to about ten carbonatoms.

Specific examples of alkyl groups are methyl, ethyl, n-propyl,isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl,isopentyl, methylbutyl, dimethylbutyl and neopentyl. Typical alkenyl andalkynyl groups may have one unsaturated bond, such as an allyl group, ormay have a plurality of unsaturated bonds, with such plurality of bondseither adjacent, such as allene-type structures, or in conjugation, orseparated by several saturated carbons.

Compounds of Formula I would be useful in control of neuropathologicalprocesses and the neuro-degenerative consequences thereof byadministering a therapeutically-effective amount of a compound ofFormula I to a subject in need of such control or treatment. A compoundof Formula I would be useful alone, or in a composition containing oneor more pharmaceutical excipients, for neuro-protective purposes such asfor controlling or treating chronic or acute neurotoxic injury or braindamage resulting from a neuro-degenerative disease. Compounds of FormulaI would be particularly useful for treating neurotoxic injury whichfollows periods of anoxia or hypoxia producing ischemia typicallyassociated with stroke, cardiac arrest, hypoglycemia or perinatalasphyxia. The phrase "therapeutically-effective amount" of a compound ofFormula I is defined as that amount of compound which produces anefficacious response in a subject afflicted with or susceptible to aneuro-degenerative disease.

In Formula I, as well as in Formulae II-V defining sub-sets of compoundswithin Formula I, there is shown an imidazo[1,2-a]pyrimidine ringsystem. Within the six-membered ring portion of this ring system, thereare substitutable positions at the 5-, 6- and 7-ring positions. In eachof Formulae I-V, there is a requirement for attachment of an acidicmoiety at one of the 5-, 6- or 7-ring positions. This acidic moiety maybe provided by a carboxylic acid or phosphorus-containing acid, or bythe amide, ester or salt derivatives of such acids which when hydrolyzedwould provide the acidic moiety. It is preferred that the acidic moietybe attached to the ring position through an alkylene group such as --CH₂-- or --CH₂ CH₂ --. Favored positions for attachment of the acidicmoiety are the 5- and 7-ring positions. The most favored position forattachment of the acidic moiety is at the 5-ring position. An Xsubstituent, selected as defined above, may be attached at one or moreof the 5-, 6- or 7-ring positions not occupied by the acidic moiety.

Also included in the family of compounds of Formula I are isomeric formsincluding diastereoisomers, including enantiomers, and thepharmaceutically-acceptable salts thereof. The term"pharmaceutically-acceptable salts" embraces salts commonly used to formalkali metal salts and to form addition salts of free acids or freebases. The nature of the salt is not critical, provided that it ispharmaceutically-acceptable. Suitable pharmaceutically-acceptable acidaddition salts of compounds of Formula I may be prepared from aninorganic acid or from an organic acid. Examples of such inorganic acidsare hydrochloric, hydrobromic, hydroiodic, nitric, carbonic, sulfuricand phosphoric acid. Appropriate organic acids may be selected fromaliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclic,carboxylic and sulfonic classes of organic acids, example of which areformic, acetic, propionic, succinic, glycolic, gluconic, lactic, malic,tartaric, citric, ascorbic, glucuronic, maleic, fumaric, pyruvic,benzoic, anthranilic, p-hydroxybenzoic, salicyclic, phenylacetic,mandelic, embonic (pamoic), methansulfonic, ethanesulfonic,2-hydroxyethanesulfonic, pantothenic, benzenesulfonic, toluenesulfonic,sulfanilic, mesylic, cyclohexylaminosulfonic, stearic, algenic,b-hydroxybutyric, malonic, galactaric and galacturonic acid. Suitablepharmaceutically-acceptable base addition salts of compounds of FormulaI include metallic salts made from aluminium, calcium, lithium,magnesium, potassium, sodium and zinc or organic salts made fromN,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine,ethylenediamine, meglumine (N-methylgluca-mine) and procaine. All ofthese salts may be prepared by conventional means from the correspondingcompound of Formula I by reacting, for example, the appropriate acid orbase with the compound of Formula I.

General Synthetic Procedures

The compounds of the invention can be synthesized according to thefollowing procedures of Schemes I-III, wherein the R and V substituentsare as defined for Formula I, above, except where further noted.##STR20##

In Scheme I, there is shown a method to synthesize the products of theinvention which starts with functionalization of the methyl radical of2-amino-4-methyl pyrimidine or 2-amino-5-methyl pyrimidine (1). Thisoperation can be conducted either by halogenation or oxidation or by anymethod deemed to transform the methyl group into a --CH₂ --W residue (2)where W stands for a good leaving group such as, for instance, anhalogen atom (Cl, Br, I) or a sulfonate ester (tosylate, mesylate, etc).Most of the time, the process will be multistep, as for example, themethyl can be oxidized into the carboxylic acid, which can be reduced tothe corresponding alcohol which in turn can be reacted with a sulfonylchloride to give the desired sulfonate ester. It could be advantageousto protect the amino function during the transformation of the methylgroup, for instance when bromination of 2-amino-4-methyl pyrimidine iscarried out with N-bromosuccinimide (NBS) bromination occurred not onlyon the methyl group but also on the position 5 of the aromatic ring.This reaction can be prevented by deactivation of the aromatic ringthrough acylation of the nitrogen by groups such as t-butyloxycarbonyl,acetyl, pivaloyl, or phthalyl. The product 2 is then reacted with atrialkylphosphite in an Arbuzov reaction or with a metallic salt of adialkylphosphite leading to the synthesis of intermediate 3. Thecyclization of 3 in the presence of ethyl-3-bromopyruvate lead toisomers which can be separated either by chromatography or by fractionalcrystallization. In the case the aromatic ring has been brominated at anearlier step, the halogen can be reduced by hydrogen gas, in basic mediain the presence of palladium on carbon. The phosphonic and carboxylicester functions can be selectively hydrolyzed by trimethylsilylhalideand one equivalent of NaOH at room temperature, respectively ##STR21##

In Scheme II, there is shown a method to prepare Compound 7 by reacting4-dialkylphosphono-3-ketobutanal (5) with a 2-amino-imidazole carboxylicester 6. Two isomers are formed but the desired isomer will be the moreabundant one. Separation of the two products can be achieved bychromatography or fractional crystallization. ##STR22##

In Scheme III, there is shown a method to prepare Compound 7 by reactingthe aldehyde 5 with 2-amino-imidazole 9 which will lead to the formationof only one produce 10. Treatment of this product with a strong basesuch as lithium diisopropylamine or potassium t-butylate leads to theintermediate anion which can be acylated by CO₂, a chloroformate or apyrocarbonate.

The following working Examples show detailed descriptions of the methodsof preparation of compounds of Formula I. These detailed preparationsfall within the scope of, and serve to exemplify, the above describedGeneral Synthetic Procedures which form part of the invention. TheseExamples are presented for illustrative purposes only and are notintended as a restriction on the scope of the invention. All parts areby weight unless otherwise indicated. In Schemes IV and V, there areshown respectively, specific methods for making compounds of theinvention as described in more detail in Examples 1 and 2, which follow.##STR23##

EXAMPLE 1 ##STR24##5-Phosphonomethyl-imidazo[1,2-a]pyrimidine-2-carboxylic acid (17)] Step1:

Synthesis of 2-Amino-5-bromo-4-(diethylphosphonomethyl)-pyrimidine (13)

2-Amino-4-methylpyrimidine (5 g, 0.046 mole) was brought to reflux for24 hours in carbon tetrachloride (50 mL) in the presence ofN-bromosuccinimide (NBS, 17.8 g, 0.1 mole) and AIBN (50 mg, 0.0003mole). TLC (SiO₂, CH₂ Cl₂ -95/EtOH-5) indicated that only bromination ofthe aromatic ring took place. More NBS (17.8 g, 0.1 mole) is added andthe reflux continued for 20 more hours. The solid was then filtered,washed twice with carbon tetrachloride (50 mL), the solvent wasevaporated under reduced pressure. Triethylphosphite 50 mL) was addedand the solution brought to reflux for one hour. The excesstriethylphosphite was evaporated under reduced pressure and the brownresidue was purified through silicagel chromatography eluting with CH₂Cl₂ -95/EtOH-5. A colorless oil was obtained.

Step 2:

Synthesis ofEthyl-6-bromo-5-(diethylphosphonmethyl)-imidazo[1,2-a]pyrimidine-2-carboxylicester (14)

2-Amino-5-bromo-4-(diethylphosphonomethyl)-pyrimidine 0.5 g, 1.7 mmole)was suspended in an ethanolic solution of ethyl bromopyruvate (250 μL, 2mmole in 45 mL). The suspension was stirred at room temperatureovernight and then brought to reflux for two hours. The solvent wasevaporated under reduced pressure, water was added and the solution wasmade basic by the addition of sodium bicarbonate. The aqueous phase wasextracted with dichloromethane (3×20 mL), the organic phase was driedover potassium carbonate and evaporated under reduced pressure. The twoisomers were separated on a silicagel chromatography column eluted withCH₂ Cl₂ -97/EtOH-3. The desired isomer 14 had the shorter retentiontime. The structure of 14 was confirmed by X-ray crystallographicanalysis.

Step 3:

Synthesis ofEthyl-5-(diethylphosphonomethyl)-imidazo[1,2-a]pyrimidine-2-carboxylicester (17)

Ethyl-6-bromo-5-(diethylphosphonomethyl)-imidazo[1,2-a]pyrimidine-2-carboxylicester (90 rag, 0.2 mmole) was introduced in a round-bottom flask withethanol (35 mL), triethylamine (100 μL) and Pd on Carbon (5%, 30 mg) .The hydrogen buret and round-bottom flask were evacuated, filled withhydrogen and the reduction mixture was stirred at room temperature untilgas absorption stopped. The catalyst was filtered through a celite bed,rinsed with ethanol and the solvent was evaporated under reducedpressure. Sodium bicarbonate was added to the residue which wasextracted with dichloromethane, dried over potassium carbonate. Thesolvent was evaporated under reduced pressure.

Step 4:

Synthesis of 5-Phosphonomethyl-imidazo[1,2-a]pyrimidine-2-carboxylicacid (18)

Ethyl-5-(diethylphosphonomethyl)-imidazo[1,2-a]pyrimidine-2-carboxylicester (70 mg, 0.2 mmole) was dissolved in dichloromethane (5 mL) andtrimethylsilyl bromide was added (200 μL, 1.5 mmole). The solution wasstirred for 24 hours at room temperature and methanol was added (20 mL).The new solution was let standing at room temperature for one hour, thesolvents were evaporated under reduced pressure, the solid residue wassuspended in aqueous NaOH (1N, 3 mL) and stirred overnight at roomtemperature. The solution was neutralized by the addition of aqueous HCl(1N, 3 mL) and poured onto a strongly basic ion-exchange column (OH⁻form). The column was washed with water and aqueous acetic acid (4N) andthe product was eluted with 4N acetic acid. The product was lyophilized(24 mg). ##STR25##

EXAMPLE 2 ##STR26##7-phosphonomethyl-imidazo[1,2-a]pyrimidine-2-carboxylic acid (19)] Step1:

Synthesis ofEthyl-6-bromo-7-(diethylphosphonomethyl)-imidazo[1,2,a]pyrimidine-2-carboxylicester (15)

2-Amino-5-bromo-4-(diethylphosphonomethyl)-pyrimidine (0.5 g, 1.7 mmole)was suspended in an ethanolic solution of ethyl bromopyruvate (250 μL, 2mmole in 45 mL). The suspension was stirred at room temperatureovernight and then brought to reflux for two hours. The solvent wasevaporated under reduced pressure, water was added and the solution wasmade basic by the addition of sodium bicarbonate. The aqueous phase wasextracted with dichloromethane (3×20 mL), the organic phase was driedover potassium carbonate and evaporated under reduced pressure. The twoisomers 14 and 15 were separated on a silicagel chromatography columneluted with CH₂ Cl₂ -97/EtOH-3. The desired isomer 15had the longerretention time.

Step 2:

Synthesis of6-Bromo-7-phosphonomethyl-imidazo[1,2-a]pyrimidine-2-carboxylic acid(18)

Ethyl-6-bromo-7-(diethylphosphonomethyl)-imidazo[1,2a]pyrimidine-2-carboxylicester 15(150 mg, 0.36 mmole) in CH₂ Cl₂ (5 mL) was mixed with TMSBr (300μL, 2.27 mmole) and let stand for 2 hours. Methanol (10 mL) was thenadded. After one hour, the solution was evaporated under reducedpressure. The residue was taken up in 1N NaOH (3 mL) and let standovernight at room temperature. The solution was neutralized by theaddition of 1N HCl (3 mL) and poured onto an ion-exchange column(strongly basic, OH⁻ form), and the column was eluted successively withwater, acetic acid (4N), then 1N HCl. The product 18 was eluted with 1NHCl. The appropriate fractions were collected, and lyophilized (21 mg).

Step 3:

Synthesis of 7-phosphonomethyl-imidazo[1,2-a]pyrimidine-2-carboxylicacid (19)

6-Bromo-7-phosphonomethyl-imidazo[1,2-a]pyrimidine-2-carboxylic acid(18) (15 mg) was introduced in a 250 mL Parr bottle with 0.5N NaOH (1mL), water (15 mL) and Pd on Carbon (5%, 20 mg). The bottle wasevacuated, filled with hydrogen and shaken for one hour at roomtemperature. The product was purified by passing through a stronglybasic ion-exchange column. The product 19 was eluted with 1N HCl.

BIOLOGICAL EVALUATION

NMDA-Selective Glutamate Binding Assay

Synaptic plasma membranes (SPM) were prepared as previously described[Monahan, J. B. and Michel, J., "Identification and Characterization ofan N-methyl-D- aspartate-specific L [³ H]glutamate Recognition Site inSynaptic Plasma Membranes, J. Neurochem., 48 , 1699-1708 (1987)]. TheSPM were stored at a concentration of 10-15 mg/ml in 0.32M sucrose, 0.5mM EDTA, 1 mM MgSO₄, 5 mM Tris/SO₄, pH 7.4, under liquid nitrogen. Theidentity and purity of the subcellular fractions were confirmed by bothelectron microscopy and marker enzymes. Protein concentrations weredetermined by using a modification of the method of Lowry [Ohnishi, S.T. and Barr, J. K., "A Simplified Method of Quantitating Proteins Usingthe Biuret and Phenol Reagents", Anal. Biochem., 86, 193-197 (1978)].The SPM were treated identically for the [³ H]AMPA (QUIS), [³ H]kainateand sodium-dependent L-[³ H]-glumatate binding assays. The SPM werethawed at room temperature, diluted twenty-fold with 50 mM Tris/acetate,pH 7.4, incubated at 37° C. for 30 minutes, and centrifuged at 100,000 gfor 15 minutes. The dilution, incubation, and centrifugation wasrepeated a total of three times. Prior to use in the NMDA specific L-[³H]-glutamate binding assay the SPM were thawed, diluted twenty fold with50 mM Tris/acetate, pH 7.4 containing 0.04% (v/v) Triton X-100,incubated for 30 minutes at 37° C. and centrifuged as described above.The Triton X-100 treated membranes were washed with 50 mM Tris/acetate,pH 7.4 and centrifuged at 100,000 g for 15 minutes a total of fourtimes. Triton X-100 treatment of the SPM resulted in a higher affinityand more consistency in this L-[³ H]glutamate binding assay. For thisreason the K_(d) for glutamate and the K_(i) values for other compoundsare lower than previously reported; however, the pharmacological profileof this binding site was unaltered. The basic procedure for the receptorsubclass binding assays was similar. This general method involved addingthe radioligand (12.5 nM L-[³ H]glutamate; 0.5 nM [³ H]kainate or 10nM[³ H]AMPA) to the appropriate concentration of the test compound andinitiating the assay by the addition of ice cold synaptic plasmamembranes (0.2-0.45 mg). The binding assays were performed in 1.5 mLcentrifuge tubes with the total volume adjusted to 1.0 mL. Additions oftest compounds were made in 50 mM Tris/acetate, pH 7.4 and incubationswere carried out at 0°-4° C. The incubation time for the NMDA and theAMPA binding assays was 10 minutes, for the kainate binding assay 60minutes and for the sodium-dependent glutamate binding assay 15 minutes.The AMPA binding assay contained 100 mM KSCN and the sodium-dependentglutamate binding assay contained 150 mM sodium acetate in addition tothe previously described reagents. To terminate the incubation, thesamples were centrifuged for 15 minutes at 12,000 g and 4° C. in aBeckman Microfuge 12. The supernatant was aspirated and the pelletedmembranes dissolved in Beckman BTS-450 tissue solubilizer for a minimumof 6 hours at room temperature. Beckman MP scintillation cocktailcontaining 7 mL/1 acetic acid was then added and the samples counted ona Beckman LS 5800 or 3801 liquid scintillation counter with automaticcorrections for quenching and counting efficiency. Nonspecific bindingwas defined as the residual binding in the presence of either excessL-glutamate (0.1-0.4 mM), kainate (0.01 mM), or NMDA (0.5 mM), and was15-25% of the total binding in the NMDA binding assay, 19-27% in theAMPA binding assay, 20-30% in the kainate binding assay and 10-15% inthe sodium-dependent binding assay. Radioligand binding to the synapticplasma membranes was analyzed using Scatchard and Hill transformationsand the K_(i) values of the compounds determined using logit-logtransformations. Calculations and regression analysis were performedusing templates developed for Lotus 1, 2, 3 as previously described[Pullan, L. M. "Automated Radioligand Receptor Binding Analysis withTemplates for Lotus", Computer Appln. Biosci., 3, 131 (1987)]. Bindingresults are reported in Table I for Example compounds of the invention.

[³ H]MK-801 Binding assay

Modulation of [³ H]MK-801 binding was performed using Triton X-100(0.04% v/v) treated rat SPM that had been extensively washed. Assayincubations were at 25° C. for 30 min. and contained 5.0 nM [³ H]MK-801,L-glutamate 10.0 nM), and various concentrations of the tested compoundof the invention in 50 mM Tris/acetate, pH 7.4. The assay was stopped byrapid filtration, using Brandel MB-48 Harvester, through Whatman GF/Bfilters treated with 0.05% polyethylenimine and the samples washed fourtimes with 2.0 mL cold buffer. The radioactivity associated with thefilter was determined by liquid scintillation spectrometry. Nonspecificbinding was defined using 60 μM MK-801. IC₅₀ were determined using alogit-log transformation of the binding data. Results are reported inTable 1.

                  TABLE I                                                         ______________________________________                                        Receptor Binding Data (IC.sub.50)                                             Compound     [.sup.3 H]GLU  [.sup.3 H]MK-801                                  Ex. #        K.sub.i (μm)                                                                              K.sub.1 (μM)                                   ______________________________________                                        1            8.8            4.6                                               2            14% inhibition @                                                                             NT                                                             10 μM                                                         ______________________________________                                         NT = Not Tested                                                          

Forebrain Ischemia Assay

This assay is used to determine the extent of protection afforded bycompound of the invention to neural brain cells subjected to ischemicconditions. Male Mongolian gerbils, 50-70 gm, are used as subjects.Compound of the invention is injected i.p. 30 minutes prior to carotidocclusion into 6 gerbils at two different doses (300 mg/kg and 500mg/kg). In preparation for surgical procedures, the animals are lightlyanesthetized with methoxyflurane and placed upside down on a heated padwith their snout within a nosecone. A 70:30 mixture of nitrous oxide andoxygen containing 0.5% halothane is circulated through the nosecone toprovide continuous anesthesia throughout the surgical procedure. Amidline incision is made in the neck and the carotid arteries areexposed. A length of suture thread is placed under each carotid. Thethread is then tightened around each carotid and pressure applied to thethread to insure flow is occluded. Flow is occluded for 4-5 minutes andthen the thread is removed. The carotids are visually inspected toconfirm that fellow has occurred. The wound is then closed withautoclips and the gerbils allowed to recover. Following surgery, thegerbils are kept alive for 7 days. They are anesthetized with 100 mg/kgsodium pentobarbital and perfused transcardially with saline (withheparin) followed by buffered formalin. The brain is removed, trimmedand prepared for histological processing. Sections (10 microns) arestained with thionin. At 7 days following this type of transient globalforebrain ischemia, damaged neurons in the vulnerable CAl region of thehippocampus will have degenerated and have been cleared away by glia.Quantification of the resulting lesion is made by counting the pyramidalcell somata in a 0.5 mm length of CAl of the hippocampus on the sectioncorresponding to P 1.7 mm in the gerbil brain atlas. Normal cell countin this region of the hippocampus in unoperated gerbils is 146 ±2. Theeffects of compound of the invention are assessed by comparing thenumber of neural cells found in the hippocampus of subjects treated withof the invention compound with the cell number found in the appropriatecontrol groups. The groups are compared by the Mann-Whitney U test [Elementary Applied Statistics, Wiley and Sons, New York (1965)]. It isexpected that cell loss would be significantly reduced in gerbils givencompound of the invention as compared to an untreated control animal.

Administration of compounds within Formula I to humans can be by anytechnique capable of introducing the compounds into the bloodstream of ahuman patient, including oral administration, and by intravenous,intramuscular and subcutaneous injections.

Compounds indicated for prophylactic therapy will preferably beadministered in a daily dose generally in a range from about 0.1 mg toabout 100 mg per kilogram of body weight per day. A more preferreddosage will be a range from about 1 mg to about 100 mg per kilogram ofbody weight. Most preferred is a dosage in a range from about 1 to about50 mg per kilogram of body weight per day. A suitable dose can beadministered, in multiple sub-doses per day. These sub-doses may beadministered in unit dosage forms. Typically, a dose or sub-dose maycontain from about 1 mg to about 100 mg of active compound per unitdosage form. A more preferred dosage will contain from about 2 mg toabout 50 mg of active compound per unit dosage form. Most preferred is adosage form containing from about 3 mg to about 25 mg of active compoundper unit dose.

The active compound is usually administered inpharmaceutically-acceptable formulation, although in some acute-caresituations a compound of Formula I may be administered alone. Suchformulations may comprise the active compound together with one or morepharmaceutically-acceptable carriers or diluents. Other therapeuticagents may also be present in the formulation. Apharmaceutically-acceptable carrier or diluent provides an appropriatevehicle for delivery of the active compound without introducingundesirable side effects. Delivery of the active compound in suchformulations may be by various routes including oral, nasal, topical,buccal and sublingual, or by parenteral administration such assubcutaneous, intramuscular, intravenous and intradermal routes.

Formulations for oral administration may be in the form of capsulescontaining the active compound dispersed in a binder such as gelatin orhydroxypropylmethyl cellulose, together with one or more of a lubricant,preservative, surface-active or dispersing agent. Such capsules ortablets may contain controlled-release formulation as may be provided ina dispersion of active compound in hydroxypropylmethyl cellulose.

Formulations for parenteral administration may be in the form of aqueousor non-aqueous isotonic sterile injection solutions or suspensions.These solutions and suspensions may be prepared from sterile powders orgranules having one or more of the carriers or diluents mentioned foruse in the formulations for oral administration.

Although this invention has been described with respect to specificembodiments, the details of these embodiments are not to be construed aslimitations. Various equivalents, changes and modifications may be madewithout departing from the spirit and scope of this invention, and it isunderstood that such equivalent embodiments are part of this invention.

What is claimed is:
 1. A method to treat neurotoxic injury in a subject,which method comprises treating a subject susceptible to neurotoxicinjury with a therapeutically-effective amount of a compound of FormulaIII: ##STR27## wherein each of Y_(m) and Y_(n) is a spacer groupindependently selected from one or more groups of the formula ##STR28##with the proviso that the total number of carbon atoms in each of Y_(m)or Y_(n) cannot exceed ten carbon atoms; wherein each of R⁹ and R¹⁰ isindependently selected from hydrido, alkyl, cycloalkyl, halo, haloalkyl,hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl and alkanoyl; wherein R⁹ andR¹⁰ may be taken together to form oxo or exomethylene; wherein each ofR¹¹ and R¹² is independently selected from hydrido, alkyl, haloalkyl,phenyl, hydroxyalkyl and alkoxyalkyl; wherein m is a number selectedfrom one to three, inclusive; wherein n is a number selected from zeroto three, inclusive;wherein X is one or more groups attachable at one ormore of the 5-, 6- and 7-ring positions of the imidazo[1,2-a]pyrimidinering system; wherein each X and T is independently selected fromhydrido, halo, alkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, alkenyl,alkynyl, phenyl, benzyl, hydroxy, hydroxyalkyl, alkoxy, phenoxy,alkoxyalkyl, benzyloxy, cyano, alkanoyl, alkylthio and arylthio,##STR29## wherein each of R¹³, R¹⁴, R¹⁵ and R¹⁶ is independentlyselected from hydrido, alkyl and phenyl; wherein each of R¹, R² and R⁶is independently selected from hydrido, alkyl, allyl, cycloalkyl,cycloalkylalkyl, phenyl and benzyl;or a pharmaceutically-acceptable saltthereof.
 2. The method of claim 1 wherein said compound is selected fromcompounds, and their pharmaceutically-acceptable salts, of the group ofcompounds consisting ofethyl 5-[(diethoxyphosphinyl)methyl]-imidazo[1,2-a]pyrimidine-2-carboxylate;5-(phosphonomethyl)-imidazo[1,2-a]pyrimidine-2-carboxylic acid; ethyl6-[(diethoxyphosphinyl)methyl]-imidazo[1,2-a]pyrimidine-2-carboxylate;6-(phosphonomethyl)-imidazo[1,2-a]pyrimidine-2-carboxylic acid; ethyl7-[(diethoxyphosphinyl)methyl]-imidazo[1,2-a]pyrimidine-2-carboxylate;7-(phosphonomethyl)-imidazo[1,2-a]pyrimidine-2-carboxylic acid; ethyl6-chloro-5-[(diethoxyphosphinyl)methyl]-imidazo[1,2a]pyrimidine-2-carboxylate;6-chloro -5-(phosphonomethyl)-imidazo[1,2-a]pyrimidine-2-carboxylicacid; ethyl7-chloro-5-[(diethoxyphosphinyl)methyl]-imidazo[1,2-a]pyrimidine-2-carboxylate;7-chloro-5-(phosphonomethyl)-imidazo[1,2-a]pyrimidine-2-carboxylic acid;ethyl 5-(diethoxyphosphinyl)-imidazo[1,2-a]pyrimidine-2-carboxylate;ethyl 5-(diethoxyphosphinyl)-imidazo[1,2-a]pyrimidine-2-carboxylate,monohydrochloride; 5-phosphono-imidazo[1,2-a]pyrimidine-2-carboxylicacid; ethyl5-[2-(diethoxyphosphinyl)-E-ethenyl]-imidazo[1,2-a]pyrimidine-2-carboxylate;5-(2-phosphono-E-ethenyl)-imidazo[1,2-a]pyrimidine-2-carboxylic acid;and 5-(2-phosphonoethyl)-imidazo[1,2-a]pyrimidine-2-carboxylic acid. 3.The method of claim 2 wherein said compound is5-Phosphonomethyl-imidazo[1,2-a]pyrimidine-2-carboxylic acid or apharmaceutically-acceptable salt thereof.
 4. The method of claim 2wherein said compound is7-phosphonomethyl-imidazo[1,2-a]pyrimidine-2-carboxylic acid or apharmaceutically-acceptable salt thereof.
 5. The method of claim 1 totreat neurotoxic injury resulting from ischemia.
 6. The method of claim1 to treat neurotoxic injury resulting from an hypoxic or anoxiccondition.
 7. The method of claim 6 wherein said hypoxic or anoxiccondition arises from stroke, cardiac arrest, hypoglycemia or perinatalasphyxia.